Patent Application
20110172639
The present invention relates generally to the field of drug delivery devices. The present invention relates specifically to a drug delivery device and method for delivery drug to the compliant layer of the skin.
An active agent or drug (e.g., pharmaceuticals, vaccines, hormones, nutrients, etc.) may be administered to a patient through various means. For example, a drug may be ingested, inhaled, injected, delivered intravenously, etc. In some applications, a drug may be administered transdermally. In some transdermal applications, such as transdermal nicotine or birth control patches, a drug is absorbed through the skin. Passive transdermal patches often include an absorbent layer or membrane that is placed on the outer layer of the skin. The membrane typically contains a dose of a drug that is allowed to be absorbed through the skin to deliver the substance to the patient. Typically, only drugs that are readily absorbed through the outer layer of the skin may be delivered with such devices.
Other drug delivery devices are configured to provide for increased skin permeability to the delivered drugs. For example, some devices use a structure, such as one or more microneedles, to facilitate transfer of the drug into the skin. Solid microneedles may be coated with a dry drug substance. The puncture of the skin by the solid microneedles increases permeability of the skin allowing for absorption of the drug substance. Hollow microneedles may be used to provide a fluid channel for drug delivery below the outer layer of the skin. Other active transdermal devices utilize other mechanisms (e.g., iontophoresis, sonophoresis, etc.) to increase skin permeability to facilitate drug delivery.
One embodiment of the invention relates to a device for delivering a drug into the skin of a subject. The device includes a drug reservoir and a microneedle having a tip, a length, and a tip sharpness. The microneedle is coupled to the reservoir. The device includes a microneedle actuator coupled to the microneedle configured to drive the microneedle into the skin of the subject upon activation. The tip sharpness and the actuator allow the microneedle to pass through an outer layer of the skin upon activation, and the length is limited such that the tip does not extend past a desired depth below the surface of the skin of the subject, where the desired depth is located in the papillary dermis or the reticular dermis.
Another embodiment of the invention relates to drug delivery device for delivering a liquid drug into the skin of a subject. The device includes a drug reservoir storing a dose of the liquid drug, a conduit coupled to the drug reservoir and a hollow microneedle having a tip, a length and a tip sharpness. The hollow microneedle is coupled to the conduit, and the conduit provides fluid communication between the drug reservoir and the hollow microneedle such that the drug is permitted to flow from the drug reservoir through the conduit and through the hollow microneedle to the skin of the subject. The device includes a microneedle actuator coupled to the hollow microneedle and configured to drive the hollow microneedle into the skin of the subject upon activation, and an engagement element configured to adhere to the skin of the subject such that the engagement element resists downward depression and/or deformation of the skin surface caused by the hollow microneedle during activation. At least one of the tip sharpness, the actuator and the engagement element is configured to reduce depression of the skin of the subject caused by the hollow microneedle following activation, and the microneedle length allows the tip (and/or the outlet) of the hollow microneedle to be delivered to the papillary dermis or reticular dermis of the subject.
Another embodiment of the invention relates to a method of delivering a drug to the skin of a subject. The method includes providing a drug delivery device. The drug delivery device includes a drug reservoir, a microneedle coupled to the reservoir and a microneedle actuator coupled to the microneedle configured to drive the microneedle into the skin of the subject upon activation. The microneedle includes a tip, a length and a tip sharpness. The method includes selecting at least one of the length, the tip sharpness and the microneedle actuator to allow the tip (and/or the outlet) to be delivered to a desired depth below the surface of the skin of the subject where the desired depth is located in the papillary dermis or the reticular dermis and activating the microneedle actuator to insert the microneedle to the desired depth within the skin of the subject. The method includes delivering the drug to the skin of the subject via the microneedle.
Alternative exemplary embodiments relate to other features and combinations of features as may be generally recited in the claims
This application will become more fully understood from the following detailed description, taken in conjunction with the accompanying figures, wherein like reference numerals refer to like elements in which:
Before turning to the figures, which illustrate the exemplary embodiments in detail, it should be understood that the present application is not limited to the details or methodology set forth in the description or illustrated in the figures. It should also be understood that the terminology is for the purpose of description only and should not be regarded as limiting.
Referring generally to the figures, a substance delivery device assembly is shown according to various exemplary embodiments. The delivery device assembly includes various packaging and/or protective elements that provide for protection during storage and transportation. The assembly also includes a substance delivery device that is placed in contact with the skin of a subject (e.g., a human or animal, etc.) prior to delivery of the substance to the subject. After the device is affixed to the skin of the subject, the device is activated in order to deliver the substance to the subject. Following delivery of the substance, the device is removed from the skin.
The delivery device described herein may be utilized to deliver any substance that may be desired. In one embodiment, the substance to be delivered is a drug, and the delivery device is a drug delivery device configured to deliver the drug to a subject. As used herein the term “drug” is intended to include any substance delivered to a subject for any therapeutic, preventative or medicinal purpose (e.g., vaccines, pharmaceuticals, nutrients, nutraceuticals, etc.). In one such embodiment, the drug delivery device is a vaccine delivery device configured to deliver a dose of vaccine to a subject. In one embodiment, the delivery device is configured to deliver a flu vaccine. The embodiments discussed herein relate primarily to a device configured to deliver a substance intradermally. In other embodiments, the device may be configured to deliver a substance transdermally or may be configured to deliver drugs directly to an organ other than the skin.
Referring to
As shown in
Referring to
In one embodiment, delivery device 16 is sized to be conveniently wearable by the user during drug delivery. In one embodiment, the length of delivery device 16 along the device's long axis is 53.3 mm, the length of delivery device 16 along the device's short axis (at its widest dimension) is 48 mm, and the height of delivery device 16 at button 20 following activation is 14.7 mm. However, in other embodiments other dimensions are suitable for a wearable drug delivery device. For example, in another embodiment, the length of delivery device 16 along the device's long axis is between 40 mm and 80 mm, the length of delivery device 16 along the device's short axis (at its widest dimension) is between 30 mm and 60 mm, and the height of delivery device 16 at button 20 following activation is between 5 mm and 30 mm. In another embodiment, the length of delivery device 16 along the device's long axis is between 50 mm and 55 mm, the length of delivery device 16 along the device's short axis (at its widest dimension) is between 45 mm and 50 mm, and the height of delivery device 16 at button 20 following activation is between 10 mm and 20 mm.
While in the embodiments shown the attachment element is shown as, but not limited to, adhesive layer 22, other attachment elements may be used. For example, in one embodiment, delivery device 16 may be attached via an elastic strap. In another embodiment, delivery device 16 may not include an attachment element and may be manually held in place during delivery of the drug. Further, while the activation control is shown as button 20, the activation control may be a switch, trigger, or other similar element, or may be more than one button, switch, trigger, etc., that allows the user to trigger delivery of the drug.
Referring to
Reservoir cover 34 includes a pair of tabs 54 and 56 that each extend inwardly from a portion of the inner edge of cover 34. Base portion 32 includes a recess 58 and second recess similar to recess 58 on the opposite side of base portion 32. As shown in
As shown in
Button 20 also includes a first support ledge 64 and a second support ledge 66 both extending generally perpendicular to the inner surface of sidewall 40. The outer surface of second support portion 63 includes a first button support surface 68 and second button support surface 70. When button 20 is mounted to second support portion 63, first support ledge 64 engages and is supported by first button support surface 68 and second support ledge 66 engages and is supported by second button support surface 70. The engagement between ledge 64 and surface 68 and between ledge 66 and surface 70 supports button 20 in the pre-activation position (shown for example in
Referring to
Substance delivery assembly 36 includes a reservoir actuator or force generating element, shown as, but not limited to, hydrogel 98, and a fluid distribution element, shown as, but not limited to, wick 100 in
Substance delivery assembly 36 includes a microneedle activation element or microneedle actuator, shown as, but not limited to, torsion rod 106, and a latch element, shown as, but not limited to, latch bar 108. As explained in greater detail below, torsion rod 106 stores energy, which upon activation of delivery device 16, is transferred to one or more microneedles causing the microneedles to penetrate the skin. Substance delivery assembly 36 also includes a fluid reservoir plug 110 and plug disengagement bar 112. Bottom wall 61 is shown removed from base portion 32, and adhesive layer 22 is shown coupled to the lower surface of bottom wall 61. Bottom wall 61 includes one or more holes 114 that are sized and positioned to align with holes 28 in adhesive layer 22. In this manner, holes 114 in bottom wall 61 and holes 28 in adhesive layer 22 form channels, shown as needle channels 116.
As shown in
Referring to
As shown in
Delivery device 16 includes an activation fluid reservoir, shown as, but not limited to, fluid reservoir 147, that contains an activation fluid, shown as, but not limited to, water 148. In the embodiment shown, fluid reservoir 147 is positioned generally below hydrogel 98. In the pre-activation position of
Referring to
With the seal broken, water 148 within reservoir 147 is put into fluid communication with hydrogel 98. As water 148 is absorbed by hydrogel 98, hydrogel 98 expands pushing barrier film 86 upward toward drug reservoir base 80. As barrier film 86 is pushed upward by the expansion of hydrogel 98, pressure within drug reservoir 88 and drug channel 90 increases. When the fluid pressure within drug reservoir 88 and drug channel 90 reaches a threshold, check valve 136 is forced open allowing drug 146 within drug reservoir 88 to flow through aperture 138 at the end of drug channel 90. As shown, check valve 136 includes a plurality of holes 140, and microneedle array 134 includes a plurality of hollow microneedles 142. Drug channel 90, hole 138, plurality of holes 140 of check valve 136, internal channel 141 of microneedle array 134 and hollow microneedles 142 define a fluid channel between drug reservoir 88 and the subject when check valve 136 is opened. Thus, drug 146 is delivered from reservoir 88 through drug channel 90 and out of the holes in the tips of hollow microneedles 142 to the skin of the subject by the pressure generated by the expansion of hydrogel 98.
In the embodiment shown, check valve 136 is a segment of flexible material (e.g., medical grade silicon) that flexes away from aperture 138 when the fluid pressure within drug channel 90 reaches a threshold placing drug channel 90 in fluid communication with hollow microneedles 142. In one embodiment, the pressure threshold needed to open check valve 136 is about 0.5-1.0 pounds per squire inch (psi). In various other embodiments, check valve 136 may be a rupture valve, a swing check valve, a ball check valve, or other type of valve the allows fluid to flow in one direction. In the embodiment shown, the microneedle actuator is a torsion rod 106 that stores energy for activation of the microneedle array until the activation control, shown as button 20, is pressed. In other embodiments, other energy storage or force generating components may be used to activate the microneedle component. For example, in various embodiments, the microneedle activation element may be a coiled compression spring or a leaf spring. In other embodiments, the microneedle component may be activated by a piston moved by compressed air or fluid. Further, in yet another embodiment, the microneedle activation element may be an electromechanical element, such as a motor, operative to push the microneedle component into the skin of the patient.
In the embodiment shown, the actuator that provides the pumping action for drug 146 is a hydrogel 98 that expands when allowed to absorb water 148. In other embodiments, hydrogel 98 may be an expandable substance that expands in response to other substances or to changes in condition (e.g., heating, cooling, pH, etc.). Further, the particular type of hydrogel utilized may be selected to control the delivery parameters. In various other embodiments, the actuator may be any other component suitable for generating pressure within a drug reservoir to pump a drug in the skin of a subject. In one exemplary embodiment, the actuator may be a spring or plurality of springs that when released push on barrier film 86 to generate the pumping action. In another embodiment, the actuator may be a manual pump (i.e., a user manually applies a force to generate the pumping action). In yet another embodiment, the actuator may be an electronic pump.
Referring to
In one embodiment, delivery device 16 and reservoir 88 are sized to deliver a dose of drug of up to approximately 500 microliters. In other embodiments, delivery device 16 and reservoir 88 are sized to allow delivery of other volumes of drug (e.g., up to 200 microliters, up to 400 microliters, up to 1 milliliter, etc.).
Referring generally to
Referring to
Microneedle array 134 includes one or more microneedles 142. In the embodiment shown, microneedles 142 are cannulated, defining a central channel 156 that places the tip of each microneedle 142 in fluid communication with internal channel 141 of microneedle array 134. As shown, holes 114 in bottom wall 61 and holes 28 in adhesive layer 22 form a plurality of channels 116. In the inactive position, each microneedle 142 is poised above and aligns with one of the channels 116.
Referring to
As torsion rod 106 begins to twist clockwise, microneedle array 134 moves downward causing each microneedle 142 to move downward through channels 116 bringing the tips of microneedles 142 into contact with the upper surface of skin 132. As torsion rod 106 continues to twist clockwise, microneedles 142 pierce skin 132 of the subject. Following activation of microneedle array 134, microneedle array 134 rests against the upper surface of bottom wall 61, and microneedles 142 extend through channels 116 and are delivered to a desired depth within skin 132.
Referring to
In one embodiment, middle layer 352 is the papillary dermis and tips 356 of microneedles 142 are delivered to the papillary dermis. In this embodiment, drug is delivered via microneedles 142 to the papillary dermis layer. The papillary dermis is believed to be more compliant than either the epidermis, represented as layer 350, or the reticular dermis, represented as layer 354. Due to the compliant nature of the papillary dermis, delivery of tips 356 of microneedles 142 to the papillary dermis may be advantageous for transdermal drug delivery. When compared to the less compliant epidermis or reticular dermis, it is believed that delivery of a drug via a microneedle to the papillary dermis may allow for a greater volume of drug to be delivered via the microneedle or for a higher drug delivery rate through the microneedle because the compliant nature of the papillary dermis allows the tissue to expand and deform as the drug is delivered. Further, it is believed that delivery of drug to the papillary dermis reduces leakage of the drug back to the surface of skin 132 during drug delivery because of the compliant nature of the papillary dermis. In one embodiment, delivery device 16 is configured to deliver tip 356 of microneedle 142 to the papillary dermis of the upper arm. In another embodiment, delivery device 16 is configured to deliver tip 356 of microneedle 142 to the papillary dermis of the thigh.
In another embodiment, middle layer 352 may be the reticular dermis and tips 356 of microneedles 142 are delivered to the reticular dermis. In one particular embodiment, tips 356 may be delivered to the upper half of the reticular dermis. Tips 356 of microneedles 142 may be delivered to the reticular dermis for applications in which delivery of drug to the reticular dermis is desired. In some embodiments, with tips 356 located in the reticular dermis, delivered drug may flow upward through the skin from tips 356. This allows the drug to be delivered to both the reticular dermis and the papillary dermis. In various embodiments, tips 356 may be delivered to various depths below the outer surface of the skin. For example, in one embodiment, tips 356 may be delivered to a depth of approximately 100 micrometers to 2 millimeters below the outer surface of the skin (e.g. the skin of the upper arm). In another embodiment, tips 356 may be delivered to a depth of approximately 100 micrometers to 1.9 millimeters below the outer surface of the skin (e.g., the skin of the abdomen). In another embodiment, tips 356 may be delivered to a depth of approximately 100 micrometers to 1.1 millimeters below the outer surface of the skin. In another embodiment, tips 356 may be delivered to a depth of approximately 250 micrometers to 950 micrometers below the outer surface of the skin. In other embodiments, tips 356 may be delivered to other depth ranges (e.g., 150 micrometers to 650 micrometers, 150 micrometers to 200 micrometers, 300 micrometers to 1.25 millimeters, etc.).
Several components of drug delivery device 16 relate to the depth of delivery of tip 356 of microneedle 142. Appropriately selecting components with particular features, properties, etc., allows one to configure delivery device 16 to deliver tip 356 of microneedle 142 to a desired depth within skin 132. Generally, the delivery depth of tip 356 depends on the length of the microneedles, the sharpness of the microneedles, the force imparted to the microneedles to penetrate the skin, the length of the channels through which the microneedles extend and the amount of depression experienced by the skin following needle penetration. The delivery depth of tip 356 also varies with the number of microneedles present on microneedle array 134.
Referring to
Needle length, NL, sets the maximum potential delivery depth. As shown in
For a given needle length and for a given channel length, the desired delivery depth, ID, is achieved by controlling the depth of skin depression, D, that remains following insertion of microneedle 142. The depth of skin depression, D, that occurs during microneedle insertion for a particular delivery device is a function of the physical properties of the skin, the sharpness of tip 356 of microneedle 142 and the force supplied by torsion rod 106. As will be explained in more detail below, in one embodiment, delivery device may include a tissue support structure that engages skin 132 to resist the downward depression and/or surface deformation caused by microneedle 142. In this embodiment, the depth of skin depression, D, is also a function of the amount of depression or deformation resistance afforded by the tissue support structure.
Skin depression D decreases as the sharpness of tip 356 increases and width of the needle decreases. Skin depression D also decreases as the force supplied to microneedle array 134 by the microneedle actuator (e.g., torsion rod 106) increases and as the velocity of tips 356 at insertion increases. Thus, for a given tip sharpness and needle length, the microneedle actuator (e.g., torsion rod 106) may be selected to deliver sufficient force to substantially reduce or to minimize skin depression. In one embodiment, the force delivered by the microneedle actuator may be selected to be above a threshold above which skin depression D no longer substantially decreases as a function of the force supplied by the microneedle actuator.
In one embodiment, the sharpness of tip 356 is selected to reduce skin depression D. In another embodiment, the forced supplied by torsion rod 106 is selected to reduce skin depression D. In one embodiment, the sharpness of tip 356 and/or the needle length of microneedles 142 may be determined primarily by the selection of a particular manufacturing technique or by selection of a particular microneedle material. In this embodiment, reduction of skin depression may be accomplished primarily by selecting the force delivered by the microneedle actuator.
Accordingly to various embodiments, the length of the portion of microneedle 142 that extends below the lower surface of adhesive layer 22 is between 0.85 mm and 1.1 mm, preferably between 0.9 mm and 1.05 mm, and more preferably between 0.95 mm and 1 mm. In one preferred embodiment, the length of the portion of microneedle 142 that extends below the lower surface of adhesive layer 22 may be 1 mm, and in another preferred embodiment, the length of the portion of microneedle 142 that extends below the lower surface of adhesive layer 22 may be 0.95 mm. In various embodiments, the radius of curvature of tip 356 (which is a measurement of tip sharpness) may be 17 μm plus or minus 8 μm. In one embodiment, the energy stored in the microneedle actuator (e.g., torsion rod 106) is between 0.015 and 0.025 J, preferably between 0.018 and 0.022 J and even more preferably between 0.019 and 0.021 J. In one preferred embodiment, the energy stored in the microneedle actuator is 0.02 J.
As noted above, reduction of skin depression D may be accomplished by providing a drug delivery device with a tissue support structure that engages skin 132 to resist the downward depression and/or surface deformation caused by microneedle 142. In the embodiment shown, the tissue support structure includes at least one channel, shown as channels 116 formed through bottom wall 61 and adhesive layer 22, a tensile membrane or rigid wall or backing, shown as, but not limited to, the portion of the rigid bottom wall 61 positioned beneath microneedle array 134, and an engagement element, shown as, but not limited to, the portion of the adhesive layer 22 adjacent to channels 116.
Referring to
In the embodiment shown in
Bottom wall 61 provides a tensile membrane or rigid support or anchor for adhesive layer 22 to pull on as adhesive layer 22 acts to resist or prevent the inward and downward depression and/or deformation of skin 132. The effectiveness of adhesive layer 22 as part of a support structure is increased as the strength of the adherence between adhesive layer 22 and the outer surface of skin 132 is increased. The effectiveness of adhesive layer 22 as part of a support structure is also increased as the edge of the adhesive layer at channel 116 is brought closer to shaft 160 of microneedle 142. Thus, the cylindrical channel 116 has a diameter minimized to match the diameter of the base of microneedle 142. In another embodiment, holes 114 in bottom wall 61 and holes 28 in adhesive layer 22 have tapered sidewalls such that the holes have a diameter that decreases in the direction toward the outer surface of adhesive layer 22 forming generally cone-shaped channels 162 having tapered sidewalls. In this embodiment, the diameters of channels 162 at the point of contact between adhesive layer 22 and skin 132 are less than in the case of the cylindrical channels. Thus, tapered channel 162 brings the edge of adhesive layer 22 at channel 162 closer to the point of contact between the tip of microneedle 142 and skin 132 than the cylindrical channels 116.
While the tissue support structure embodiments discussed herein include a layer of adhesive to adhere to the skin to provide support to and to resist inward and downward depression or deformation of the skin surface caused by contact with the microneedle, other skin engagement elements may be used that resist the skin deformation and/or depression. For example in one embodiment, the lower surface of bottom wall 61 below microneedle array 134 may include hook structures to engage the skin adjacent to channels 116 to resist skin surface depression or deformation. In another embodiment, the lower surface of bottom wall 61 below microneedle array 134 may include clamp or pinch structures to engage the skin adjacent to channels 116 to resist skin surface depression or deformation.
Skin depression D may be reduced via a tissue support structure as discussed above. In one embodiment of a drug delivery device 16 including a tissue support structure, needle length, tip sharpness and the force delivered by the microneedle actuator may be less than would otherwise be needed. In one embodiment, needle length, sharpness of tip 356 and the force generated by a microneedle actuator (e.g., by selecting spring materials, spring configurations, etc.), are selected to deliver tip 356 to a desired depth. In another embodiment, delivery device 16 includes a support structure that resists deformation of skin 132 caused by microneedle 142, and needle length, sharpness of tip 356 and the force generated by the microneedle actuator (e.g., torsion rod 106) are selected to deliver tip 356 to a desired depth. Further, the amount of the decrease in skin depression D caused by the tissue support structure may be selected such that tip 356 of microneedle 142 is delivered to a predetermined or desired depth within skin 132. In one embodiment, tip sharpness and the actuator may be configured such that tip 356 of the microneedle passes through the outer layer of the skin upon activation, and the needle length is limited such that the tip does not extend past a desired depth within the skin of the subject. In one embodiment, the desired depth is selected such that tip 356 of microneedle 142 is delivered to the papillary dermis.
Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only. The construction and arrangements of the drug delivery device assembly and the drug delivery device, as shown in the various exemplary embodiments, are illustrative only. Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.) without materially departing from the novel teachings and advantages of the subject matter described herein. Some elements shown as integrally formed may be constructed of multiple parts or elements, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. The order or sequence of any process, logical algorithm, or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes and omissions may also be made in the design, operating conditions and arrangement of the various exemplary embodiments without departing from the scope of the present invention.
